Synthesis, Receptor Binding, and Tissue Distribution of 7α- and 11β-Substituted (17α,20E)- and (17α,20Z)-21-125I>odo-19-norpregna-1,3,5(10),20- tetraene-3,17-diols

Article abstract of DOI:10.1021/jm00106a054

The 11β-methoxy, 11β-ethoxy, and 7α-methyl derivatives of the isomeric (17α,20E)- and (17α,20Z)-(iodovinyl)estradiols 3 and 6, and their no-carrier-added <125I>iodovinyl analogues, were evaluated for their relative target-tissue retension and binding affinity for the estrogen receptor.The isomeric iodovinyl and <125I>iodovinyl derivatives were prepared via destannylation of the corresponding tributylstannyl precursors in the presence of H2O2 or chloroamine-T, with retension of configuration.The 20Z isomers 6 exhibited slightly higher receptor binding affinities than the 20E isomers 3, with all eight isomeric products giving relative binding affinity values in the 20-50 range.The 11β- and 7α-substituted (iodovinyl)estradiols gave substantially higher estrogen receptor-mediated uterus uptake as compared to the nonsubstituted parent molecule.Synergism between the effect of 11β- or 7α-substituents and the configuration of the iodovinyl group was evident from the in vivo distribution pattern of <125I>-3 and -6.The best uterus uptake was observed, at 2 h postinjection, with the 20E isomer of 11β-methoxy derivative 3b.However, at 5 h postinjection the 20Z isomer 6b reached higher uterus concentrations than the 20E isomer 3b, and furthermore, these values are now comparable to those observed with the 20Z isomer of the 11β-ethoxy derivative 6c.In the case of the 7α-methyl derivatives the differences in in vivo stability between the 20E and 20Z isomers was less pronounced, whereas the 20Z isomer 6d reached somewhat higher uterus to blood as well as nontarget ratios.